Wakefulness Finds a Powerful Ally

By ANAHAD O'CONNOR

Laurie Coots, a marketing executive who flies to meetings in other countries twice a week, spent years trying to conquer sleepless nights and chronic jet lag. But nothing worked, she says, and every day was a struggle to stay awake.

"It was debilitating," said Ms. Coots, 46, who is from Los Angeles. "I couldn't give an effective presentation because I was always shaky and nervous from being amped up on caffeine and stimulants."

Then she found modafinil, a small white pill that revs up the central nervous system without the jitteriness of caffeine or the addiction and euphoria of amphetamines.

"Without it my life would not be possible," she said.

Since 1998, modafinil, made by Cephalon and sold under the brand name Provigil, has quietly altered the lives of millions of people. No one knows exactly how it works, but sales of the drug are skyrocketing.

People who take it say it keeps them awake for hours or even days. It has been described as a nap in the form of a pill, making most users feel refreshed and alert but still able to go to bed when they are ready. And because its side effects are rarely worse than a mild headache or slight nausea, experts fear that it has rapidly become a tempting pick-me-up to a nation that battles sleep with more than 100 million cups of coffee a day.

Few numbers are available, but experts say that as modafinil grows more widely available, it is becoming a fixture among college students, long-haul truckers, computer programmers and others determined to burn the midnight oil. Some worry that an array of common disorders, like diabetes and sleep apnea, will go undiagnosed if doctors dole out Provigil instead of seeking the underlying diseases that cause fatigue.

In a culture of 24-hour stores, graveyard shifts and coffee shops on every corner, modafinil might also pose a more subtle danger: to the countless Americans in search of an extra edge, modafinil could be a cure for sleep.

"This drug enables us to be that much more workaholic and that much more obsessed with accomplishments and productivity, and I think our society is already extreme along those lines," said Dr. Martha J. Farah, director of the Center for Cognitive Neuroscience at the University of Pennsylvania. "The natural checks on that tendency, like needing to go to bed, are being rolled back by modafinil."

To the extent that modafinil becomes the latest lifestyle drug, as ubiquitous as Viagra, scientists warn that cutting back on sleep, even by one hour a night, can have long-term neurological and cardiovascular effects that are only now being recognized.

"It's almost fortuitous that at the same time that this drug has come out, we have increasing mounds of data showing that sleep is a restorative, protective health process," said Dr. Neil B. Kavey, director of the Sleep Disorders Center at Columbia Presbyterian Medical Center. "It affects performance, blood pressure, heart rate, insulin, various hormone secretions. No matter what medications come out that make sleep seem like a waste of time, we know that the sleep-deprived state is a bad one to be in."

Discovered by French researchers in the late 1970's, modafinil went on the market in the United States in 1998 as a treatment for narcolepsy, a severe sleep disorder. Earlier this year, the Food and Drug Administration broadened its approved uses to include obstructive sleep apnea, a narrowing or blockage of the airways, and sleeping problems caused by shift work. An effort by Cephalon to have the drug approved for a third indication, excessive sleepiness from any cause, was rejected.

But the three conditions modafinil is approved to treat make up only a fraction of its total uses. According to Cephalon, based in West Chester, Pa., 90 percent of all prescriptions for the drug are for "off-label" uses, including fatigue, depression, attention deficit hyperactivity disorder, and sleepiness caused by other prescription medications.

In the last year, six American track and field athletes have tested positive for the substance, which is on the United States Olympic Committee's list of banned stimulants. One group of scientists is testing its effectiveness as an appetite suppressant in people who are overweight. And a government-financed study found that it blunts the high produced by cocaine, making it a promising treatment for addiction.

"The off-label use of this drug is staggering," said Dr. Eric Heiligenstein, a psychiatrist at the University of Wisconsin who studies substance abuse by teenagers.

"This is a very clean drug that affects all the things that help people with their cognitive functioning," he said. "The main barrier to more widespread use is that it's expensive, which will change as more insurance companies start to cover it."

For doctors, modafinil's biggest lure is its safety profile. It was used in France for several years without reports of major problems before reaching the United States. In clinical trials, only about 1 percent of people complained of side effects, including nausea, mild headache and nervousness.

But scientists point out that as with any drug, more serious side effects could appear as modafinil is used more widely.

"I'm not aware of any terrible outcomes, but I don't think there have been enough long-term studies of modafinil to rule out all dangers," said Dr. Jerome M. Siegel, chief of neurobiology research at the Veterans Affairs Greater Los Angeles Healthcare System.
Total worldwide sales of Provigil soared above $290 million in 2003, up from $207 million in 2002. Marc Goodman, a pharmaceutical analyst at Morgan Stanley, expects that figure to reach $409 million this year. More than 90 percent of that revenue, he said, will come from sales in the United States alone.

"If you look back before the drug was launched, no one would ever have believed it would be this big," Mr. Goodman said. "Everyone viewed narcolepsy as the market and didn't appreciate the benign side-effect profile and how that would play into off-label uses."

Between 2002 and 2003, Provigil's share of the stimulants market grew by 39 percent, according to IMS Health, a company that tracks the pharmaceutical industry.

In the near future, modafinil could find its way into even more medicine cabinets. Mr. Goodman said it was likely that Cephalon's patent for the compound would be challenged by several drug companies seeking to market generic versions. If they succeed, it would increase the availability of modafinil and almost certainly drive down the price of a monthly supply, which is now $120 or more.

Cephalon is working on Provigil's successor, a longer lasting version the company calls Nuvigil. It also hopes to win approval for modafinil as a treatment for children with attention deficit disorder, the most commonly diagnosed behavioral disorder of childhood. Some experts think this would open the door to the drug becoming even more of a household name.

Of all the questions surrounding modafinil, perhaps the most intriguing is how it works. After more than two decades of research, scientists are still trying to figure out just how it manipulates the brain.

"It is amazing that this drug has become so widely used without any real understanding of the basic science behind it," Dr. Siegel said.

Researchers know that modafinil is distinctly different from conventional stimulants, which ramp up arousal and set off a flurry of activity throughout the brain. Such stimulants, like cocaine and amphetamines, for example, produce wakefulness but also produce a high and can lead to dependence. Modafinil appears to steer clear of those side effects by aiming at specific structures and chemicals.

One neurotransmitter that is thought to be involved is dopamine, which mediates the reward pathways in the brain, producing euphoria, pleasure and addiction. Cocaine and amphetamines cause a surge in dopamine levels, while modafinil's effects are much weaker. A study of animals lacking a protein that helps process dopamine found that they did not respond to modafinil.

Dr. Thomas Scammell, an associate professor of neurology at Harvard's medical school who was involved in preclinical trials of the drug, believes that modafinil may home in on a single poorly understood dopamine circuit that is specific for wakefulness, while amphetamines and other stimulants activate all three of the brain's dopamine pathways, including those involved in addiction and locomotor activity. That selectivity, he said, might be crucial in modafinil's lack of unwanted side effects.

"I think it is a subtle enough drug that it doesn't just activate everything," he said.

Modafinil's impact on the brain is so subtle that brain scans of people who have taken it hardly register any change in activity at all. Give them amphetamine or a drug for Parkinson's disease, Dr. Scammell said, and "the changes in brain function are spectacular," but give them modafinil, and they show little more than ordinary wakefulness.

Most scientists suspect that at least three other transmitters are involved. One of them, histamine, is responsible for the sleep-inducing effects of many cold and allergy medications. In a study last month, Dr. Siegel, who is also a professor of psychiatry and biobehavioral sciences at the University of California at Los Angeles, found that histamine in the brain helps control consciousness.

In the rapid-eye-movement stage of sleep, lower levels of norepinephrine and serotonin keep the body still, producing the characteristically slack muscle tone of sleep. Lower levels of histamine, however, specifically reduce consciousness and awareness. In studies on animals last year, Japanese researchers found that modafinil releases histamine. French researchers this year found that it elevates levels of norepinephrine. And a smaller number of scientists suspect minor involvement by orexin, a substance that is severely depleted in narcoleptics.

Several researchers, including Dr. Siegel, have proposed a unified theory suggesting that all these chemicals are necessary for modafinil to take effect.

"Many things have to work together to achieve alertness," he said. "Modafinil might activate dopamine, which then activates norepinephrine, which then activates histamine, for example. But we still want to know where the initial action is."

Scientists think that the chain of reactions set off by modafinil leads to the hypothalamus, a small structure embedded in the forebrain that controls the body's hormones and regulatory functions. One part of the hypothalamus, known as the ventrolateral preoptic nucleus, appears to act as the body's sleep generator. When it is active, it produces a chemical, GABA, that inhibits the firing of cells involved in wakefulness and arousal. Scientists suspect that by increasing norepinephrine levels, modafinil may block the region from promoting sleep.

Just next door, in the posterior hypothalamus, are bundles of thousands of neurons that produce histamine. Damage to this region, scientists have found, causes excessive sleepiness. Dr. Rod Hughes, senior director of scientific communications for Cephalon, thinks the histamine center may generate wakefulness, counteracting the effects of its sleep-inducing neighbor. Modafinil might increase output in this region, coaxing a tired body into switching on its natural alertness system.

Some scientists say that regularly manipulating this system to skimp on sleep could have dire consequences. Studies have shown that chronic sleep deprivation damages health, weakening the immune system and increasing the likelihood of illness. It is also associated with a shorter life span.

But other experts counter that Americans will continue to cut back on sleep, whether they have modafinil or not. The toll of this deprivation has been visible for years on the nation's highways, where impaired judgment from sleepiness is blamed for about 100,000 accidents a year. Lack of sleep is also believed to have played a role in the space shuttle Challenger disaster, the nuclear meltdown at Chernobyl and the Exxon Valdez oil spill.

"In terms of error rate, 18 hours of no sleep, which many of us regularly do, is equivalent to a blood alcohol level of about .05," said Dr. Ronald Chervin, who was involved in clinical trials of modafinil and is the director of the University of Michigan sleep disorders center. "Twenty-one hours of no sleep is equivalent to a blood alcohol level of .08, which is illegal in many states."

If someone is falling asleep on the highway, and has no other option than driving to work, Dr. Chervin said, "I think many sleep experts would give that patient modafinil, and I think many do."

Dr. Farah, at the Center for Cognitive Neuroscience, is more concerned about the people who are taking modafinil simply so they can get ahead at work or finish a term paper. As it becomes more and more popular to use it for those reasons, she said, people might feel they have to take it just to seem as if they are performing normally.

"It would be a shame for a generation of young adults to come of age believing that the only way they can take on a challenging project is with some kind of pharmacological help," she said. "It's quite possible that modafinil will be the next Ritalin on campus, something that kids go off to college with. If it is widely used for A.D.H.D., then it will probably end up being readily available to the undergraduate masses."